Azaindoles having serotonin receptor affinity

ABSTRACT

Described herein are compounds with affinity for the 5-HT 6  receptor, which have the general formula I:                    
     wherein: 
     R represents a group of Formula II or Formula III; 
     one of A, B D or E is a N atom, the remainder being CH groups; 
     R 1  is selected from the group consisting of SO 2 Ar, C(O)Ar, CH 2 Ar and Ar; 
     R 2 , R 3  and R 4  are independently selected from the group consisting of H and alkyl; 
     ----- represents a single or double bond, with the proviso that there is only one double bond in the ring at a time; 
     n is an integer of from 1-3; 
     Z is selected from the group consisting of C, CH and N, provided that when ----- is a double bond, Z is C and when ----- is a single bond, Z is selected from CH and N; 
     Ar is an optionally substituted aryl group; 
     with the proviso that when R is a group of Formula II, R 1  is SO 2 Ar. 
     Also described is the use of these compounds as pharmaceuticals to treat indications where inhibition of the 5-HT 6  receptor is implicated, such as schizophrenia.

This invention relates to azaindole compounds having affinity forserotonin receptors, to pharmaceutical and diagnostic compositionscontaining them and to their medical use, particularly in the diagnosisand treatment of CNS conditions.

According to one aspect of the invention, there are provided compoundsof Formula I and a salt, solvate of hydrate thereof:

wherein:

R represents a group of Formula II or Formula III;

one of A, B D or E is a N atom, the remainder being CH groups;

R₁ is selected from the group consisting of SO₂Ar, C(O)Ar, CH₂Ar and Ar;

R₂, R₃ and R₄ are independently selected from the group consisting of Hand alkyl;

----- represents a single or double bond, with the proviso that there isonly one double bond in the ring at a time;

n is an integer of from 1-3;

Z is selected from the group consisting of C, CH and N, provided thatwhen ----- is a double bond, Z is C and when ----- is a single bond, Zis selected from CH and N;

Ar is an optionally substituted aryl group;

with the proviso that when R is a group of Formula II, R₁ is SO₂Ar.

It is an aspect of the invention to provide compounds which bind to the5-HT₆ receptor.

Certain compounds of the invention also bind to the 5-HT₇ receptor, anda further object of the invention provides such compounds having mixed5-HT₆ and 5-HT₇ activity.

According to another aspect of the invention, there are providedpharmaceutical compositions comprising a compound of Formula I, in anamount effective to antagonize the 5-HT₆ receptor, and apharmaceutically acceptable carrier.

In another aspect of the invention there are provided compositionscontaining a compound of Formula I, in amounts for pharmaceutical use,to treat CNS conditions where a 5-HT₆ antagonist is indicated, forexample, for the treatment or prevention of central nervous systemdisturbances such as psychosis, schizophrenia, manic depression,depression, neurological disturbances, memory disturbances,Parkinsonism, amylotrophic lateral sclerosis, Alzheimer's disease andHuntington's disease.

In another aspect of the invention, there are provided compounds usefulas intermediates in the preparation of a compound of Formula I, andhaving a general structure according to Formula IV:

wherein

R represents a group of Formula II or Formula III;

one of A, B D or E is a N atom, the remainder being CH groups;

R₂, R₃ and R₄ are independently selected from the group consisting of Hand alkyl;

----- represents a single or double bond, with the proviso that there isonly one double bond in the ring at a time;

n is an integer of from 1-3;

Z is selected from the group consisting of C, CH and N, provided thatwhen ----- is a double bond, Z is C and when ----- is a single bond, Zis selected from CH and N.

These and other aspects of the present invention are described ingreater detail hereinbelow.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

The term “alkyl” as used herein means straight and branched chain alkylradicals containing from one to six carbon atoms and includes methyl,ethyl, propyl, isopropyl, t-butyl and the like.

The term “alkoxy” as used herein means straight and branched chainalkoxy radicals containing from one to six carbon atoms and includesmethoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy and the like.

The term “aryl” as used herein means an optionally substituted 5-10membered mono- or bi-cyclic aromatic group which can contain up to 2heteroatoms, wherein the optional substituents are independentlyselected from 1-4 members of the group consisting of halo, hydroxy,alkyl, alkoxy, thioalkyl, trifluoromethyl and trifluoromethoxy, andincludes phenyl, naphthyl, indanyl, indolyl, quinolyl, furyl, thienyland the like.

The term halo as used herein means halogen and includes fluoro, chloro,bromo, iodo and the like, in both radioactive and non radioactive forms.

The term “pharmaceutically acceptable salt” means an acid addition saltwhich is compatible with the treatment of patients.

A “pharmaceutically acceptable acid addition salt” is any non-toxicorganic or inorganic acid addition salt of the base compoundsrepresented by Formula I. Illustrative inorganic acids which formsuitable salts include hydrochloric, hydrobromic, sulfuric andphosphoric acid and acid metal salts such as sodium monohydrogenorthophosphate and potassium hydrogen sulfate. Illustrative organicacids which form suitable salts include the mono-, di- andtri-carboxylic acids. Illustrative of such acids are, for example,acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric,malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic,hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic,p-toluenesulfonic acid and other sulfonic acids such as methanesulfonicacid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid saltscan be formed, and such salts can exist in either a hydrated, solvatedor substantially anhydrous form. In general, the acid addition salts ofa compound of Formula I are more soluble in water and varioushydrophilic organic solvents, and generally demonstrate higher meltingpoints in comparison to their free base forms. The selection criteriafor the appropriate salt will be known to one skilled in the art. Othernon-pharmaceutically acceptable salts, e.g. oxalates, may be used forexample in the isolation of compounds of Formula I for laboratory use,or for subsequent conversion to a pharmaceutically acceptable acidaddition salt. It should be noted that compounds of Formula I wherein Zis N are not stable in the presence of strong acid (for example 1N HCl),therefore when preparing acid addition salts of such compounds, caremust be taken to select an appropriately mild acid, for example citricacid.

“Solvate” means a compound of Formula I, or the pharmaceuticallyacceptable salt of a compound of Formula I, wherein molecules of asuitable solvent are incorporated in a crystal lattice. A suitablesolvent is physiologically tolerable at the dosage administered as thesolvate. Examples of suitable solvents are ethanol, water and the like.When water is the solvent, the molecule is referred to as a hydrate.

The term “stereoisomers” is a general term for all isomers of theindividual molecules that differ only in the orientation of their atomsin space. It includes mirror image isomers (enantiomers), geometric(cis/trans) isomers and isomers of compounds with more than one chiralcentre that are not mirror images of one another (diastereomers).

The term “treat” or “treating” means to alleviate symptoms, eliminatethe causation of the symptoms either on a temporary or permanent basis,or to prevent or slow the appearance of symptoms of the named disorderor condition.

The term “therapeutically effective amount” means an amount of thecompound which is effective in treating the named disorder or condition.

The term “pharmaceutically acceptable carrier” means a non-toxicsolvent, dispersant, excipient, adjuvant or other material which ismixed with the active ingredient in order to permit the formation of apharmaceutical composition, i.e., a dosage form capable ofadministration to the patient. One example of such a carrier is apharmaceutically acceptable oil typically used for parenteraladministration.

The term “schizophrenia” means schizophrenia, schizophreniform disorder,schizoaffective disorder and psychotic disorder wherein the term“psychotic” refers to delusions, prominent hallucinations, disorganizedspeech or disorganized or catatonic behavior. See Diagnostic andStatistical Manual of Mental Disorder, fourth edition, AmericanPsychiatric Association, Washington, D.C.

The present invention includes within its scope prodrugs of thecompounds of Formula I. In general, such prodrugs will be functionalderivatives of the compounds of Formula I which are readily convertiblein vivo into the required compound of Formula I. Conventional proceduresfor the selection and preparation of suitable prodrug derivatives aredescribed, for example, in “Design of Prodrugs” ed. H. Bundgaard,Elsevier, 1985.

Compounds of Formula I include those in which R₁ is selected from thegroup consisting of SO₂Ar, C(O)Ar, CH₂Ar and Ar, wherein Ar is anoptionally substituted aryl group. Preferably, R₁ is an SO₂Ar group or aC(O)Ar group. More preferably, R₁ is an SO₂Ar group. Preferably Ar isselected from substituted phenyl and naphthyl, more preferably alkyl- orhalo-substituted phenyl or naphthyl. Most preferably, Ar is a naphthylgroup.

When R is a group of Formula II, R₂ and R₄ are preferably H or alkyl.More preferably, R₂ is H and R₄ is methyl. Further, in preferredembodiments of Formula II Z is a carbon-containing group. In morepreferred embodiments, Z is C and one of ----- represents a double bond.Specifically, Formula II represent a group such as1-methyl-1,2,5,6-tetrahydro-pyridin-4-yl or 1-methyl-piperidin-4-yl.

Compounds of Formula I include those in which R is a group of FormulaIII. Preferably n is 1 or 2. Again, Z is, preferably, acarbon-containing group. More preferably, Z is C and one of -----represents a double bond. Preferably R₂ and R₃ are H or alkyl, morepreferably both are H. Specifically, Formula III represents a group suchas 1,2,3,5,8,8a-hexahydro-7-indolizinyl, octahydro-7-indolizinyl,1,6,7,8,9,9a-hexahydro-4-quinolizinyl or octahydro-2-quinolizinyl.

In a further embodiment of the invention, compounds of Formula Iencompass those in which halo is selected from non-radioactive halo andradioactive halo. When halo is radioactive halo, it may be, for example,radioactive iodo.

Specific embodiments of Formula I include:

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-4-azaindole;

3-(Octahydro-7-indolizinyl)-1H-4-azaindole;

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-4-azaindole;

3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-4-azaindole;

3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-4-azaindole;

1-(2,6-Dichlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole;

1-(2,6-Dichlorobenzoyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-azaindole;

1-(2,6-Dichlorobenzoyl)-3-(1-methyl-4-piperidinyl)-5-azaindole;

1-(2,6-Dimethoxylbenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole;

1-(2-Chlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole;

1-(4-Chlorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl-5-azaindole;

1-(4-Fluorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole;

1-Benzoyl-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole;

1-(1-Naphthalenesulfonyl)-3-(octahydro-8-quinolizinyl)-5-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(4-methylbenzenesulfonyl)-5-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-5-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-5-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-benzenesulfonyl-5-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-5-azaindole;

3-(1,2,4,6,7,9a-Hexahydro-2H-quinolizine-2-yl)-5-azaindole;

3-(1-Methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1-benzenesulfonyl-5-azaindole;

3-(1-Methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-azaindole;

3-(1-Methyl-4-piperidinyl)-5-azaindole;

3-(1-Methyl-4-piperidinyl)-1-benzenesulfonyl-5-azaindole;

3-(Octahydro-7-indolizinyl)-1H-5-azaindole;

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-5-azaindole;

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-5-azaindole;

3-(Octahydro-7-indolizinyl)-1-benzenesulfonyl-5-azaindole;

3-(Octahydro-7-indolizinyl)-1-benzenesulfonyl-5-azaindole;

3-(Octahydro-7-indolizinyl)-2,5-dichlorobenzenesulfonyl-5-azaindole;

3-(Octahydro-7-indolizinyl)-2,5-dichlorobenzenesulfonyl-5-azaindole;

3-(Octahydro-7-indolizinyl)-2,5-dichlorobenzenesulfonyl-5-azaindole;

3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-5-azaindole;

3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-5-azaindole;

3-(Octahydro-quinolizine)-1H-5-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-6-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-6-azaindole;

3-(Octahydro-7-indolizinyl)-1H-6-azaindole;

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-6-azaindole;

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-6-azaindole;

1-(2,6-Dichlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindole;

1-(2,6-Dimethoxylbenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindole;

1-(4-Chlorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindole;

1-(4-Fluorobenzoyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole;

1-(4-Fluorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindole;

1-(4-Fluorobenzenesulfonyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole;

1-(4-Methoxybenzoyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole;

1-(4-Methoxybenzenesulfonyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole;

1-Benzoyl-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindole;

1-Benzoyl-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(4-methylbenzenesulfonyl)-7-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-7-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-7-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-benzenesulfonyl-7-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-7-azaindole;

3-(1-Methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1-benzenesulfonyl-7-azaindole;

3-(Octahydro-7-indolizinyl)-1H-7-azaindole;

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-7-azaindole;

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-7-azaindole;

3-(Octahydro-7-indolizinyl)-1-benzenesulfonyl-7-azaindole;

3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-7-azaindole; and

3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-7-azaindole.

In preferred embodiments of the invention, the compounds of Formula Iinclude:

1-(2,6-Dichlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-azaindole;

1-(2,6-Dichlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-azaindole;

1-(2,6-Dichlorobenzoyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-5-azaindole;

1-(2,6-Dichlorobenzoyl)-3-(1-methyl-4-piperidinyl)-1H-5-azaindole;

1-(2,6-Dimethoxylbenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-azaindole;

1-(2,6-Dimethoxylbenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-azaindole;

1-(2-Chlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-azaindole;

1-(4-Fluorobenzoyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole;

1-(4-Methoxybenzoyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole;

1-Benzoyl-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-azaindole;

1-Benzoyl-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-azaindole; and

1-Benzoyl-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole.

In more preferred embodiments of the invention, the compounds of FormulaI include:

1-(4-Chlorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl-1H-7-azaindole;

1-(4-Chlorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl-1H-5-azaindole;

1-(4-Fluorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-azaindole;

1-(4-Fluorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-azaindole;

1-(4-Fluorobenzenesulfonyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole;

1-(4-Methoxybenzenesulfonyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(4-methylbenzenesulfonyl)-1H-7-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(4-methylbenzenesulfonyl)-1H-5-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-benzenesulfonyl-1H-5-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-benzenesulfonyl-1H-7-azaindole;

3-(1-Methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1-benzenesulfonyl-1H-5-azaindole;

3-(1-Methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1-benzenesulfonyl-1H-7-azaindole;

3-(1-Methyl-4-piperidinyl)-1-benzenesulfonyl-1H-5-azaindole;

3-(Octahydro-7-indolizinyl)-1-benzenesulfonyl-1H-5-azaindole;

3-(Octahydro-7-indolizinyl)-1-benzenesulfonyl-1H-7-azaindole; and

3-(Octahydro-7-indolizinyl)-2,5-dichlorobenzenesulfonyl-1H-5-azaindole.

In the most preferred embodiments of the invention, the compounds ofFormula I include:

1-(1-Naphthalenesulfonyl)-3-(octahydro-4-quinolizinyl)-1H-5-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-1H-6-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-1H-7-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-1H-5-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-1H-5-azaindole;

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-1H-7-azaindole;

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-1H-4-azaindole;

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-1H-5-azaindole;

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-1H-6-azaindole;

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-1H-7-azaindole;

3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-1H-4-azaindole;

3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-1H-5-azaindole;and

3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-1H-7-azaindole.

Compounds of Formula I may have at least one asymmetric centre. Wherethe compounds according to the invention have one asymmetric centre theymay exist as enantiomers. Where the compounds according to the inventionpossess two or more asymmetric centres, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof in any proportion are encompassed within the scope of thepresent invention.

The conversion of a given compound salt to a desired compound salt isachieved by applying standard techniques, in which an aqueous solutionof the given salt is treated with either a solution of a base e.g.sodium carbonate or potassium hydroxide, or an acid, e.g. HCl (cautionwhen Z═N), to liberate the neutral compound which is then extracted intoan appropriate solvent, such as ether. The neutral compound is thenseparated from the aqueous portion, dried, and treated with therequisite acid or base to give the desired salt.

Also included within the scope of the invention are solvates of theinvention. The formation of the solvate will vary depending on thecompound and solvent used. In general, solvates are formed by dissolvingthe compound in the appropriate solvent and isolating the solvate bycooling or using an antisolvent. The solvate is typically dried orazeotroped under ambient conditions.

Prodrugs of compounds of Formula I may be conventional esters withavailable hydroxyl (or thiol) or carboxyl groups. For example, if asubstituent of a compound of Formula I is, or contains, a hydroxylgroup, it may be acylated using an activated acid in the presence of abase and, optionally, in inert solvent (e.g. an acid chloride inpyridine). Some common esters which have been utilized as prodrugs arephenyl esters, aliphatic (C₁-C₂₄) esters, acyloxymethyl esters,carbamates and amino acid esters.

In accordance with other aspects of the invention, the compounds of thepresent invention can be prepared by processes analogous to thoseestablished in the art.

For example, as shown in Scheme 1, compounds of Formula I (wherein R′ isSO₂Ar, C(O)Ar or CH₂Ar) may be prepared by first treating compounds ofFormula IV with a suitable base, followed by the addition of reagentR′—Y, where Y is a suitable leaving group such as halo, arylsulfonyloxyor alkylsulfonyloxy. Preferably Y is chloro. Suitable bases includesodium hydride, lithium diisopropylamide, n-butyllithium or sodiumbis(trimethylsilyl)amide, the reaction being carried out in an inertsolvent such as dimethyl formamide, tetrahydrofuran or hexanes at atemperature in the range of −100 to 30° C. Alternatively an organicamine in the presence of 4-dimethylaminopyridine (DMAP) can be used, thereaction being carried out in an inert solvent such as methylenechloride or chloroform, at a temperature in the range of 0-60° C.Preferred conditions are sodium bis(trimethylsilyl)amide intetrahydrofuran at temperatures in the range of 0° C. to roomtemperature, or triethylamine and DMAP in methylene chloride at roomtemperature. Reagents R′—Y are commercially available or can be preparedusing standard methods known to those skilled in the art. Thepreparation of compounds of Formula IV is described below.

Compounds of Formula I wherein R₁ is Ar may be prepared as shown inScheme 2, below. Treatment of IV with an aryl halide (wherein Ar is asdefined in Formula I) under standard Ullmann arylation conditions, forexample in the presence of a base such as potassium carbonate and acatalyst such as copper, copper (I) iodide or copper (I) bromide ormixtures thereof, in an inert solvent such as N-methylpyrrolidinone(NMP), dimethylformamide (DMF), hexamethyl-phosphoramide (HMPA) ordimethylsulfoxide (DMSO) at temperatures in the range of 150-200° C.Preferred conditions are copper (I) bromide and copper in NMP attemperatures in the range of 160-170° C.

Compounds of Formula IV wherein R is a group of Formula III may beprepared by a number of routes. For example, as shown in Scheme 3,below, compound A (where PG is a suitable protecting group), may becondensed with reagent B, under acidic conditions, to provideregioisomeric products C and C′. The reaction is carried out in asuitable solvent, at temperatures in the range of 25-100° C., preferablywithin the range 60-90° C. Suitable conditions include, for example,trifluoroacetic acid in acetic acid at a temperature in the range of50-120° C., preferably at around 110° C.

Under these reaction conditions both regioisomeric alkenes C and C′ maybe isolated, the ratio of which will vary according to the reactionconditions and the identity and position of R₂. When R₂ is H, this ratiois typically 1:1.

Compounds C and C′ may be reduced under standard conditions (using, forexample, metal hydrides) to provide compounds D. Preferred is reductionby hydrogenation, using a suitable catalyst such as palladium orplatinum on carbon in methanol or ethanol at room temperature. CompoundsD can exist in isomeric forms which may be separable, for example bycolumn chromatography, to yield so-called less polar and more polarisomers.

Deprotection of compound D under standard conditions yields compound IV.For example, when PG is an acetate group, this can be hydrolyzed undereither basic or acidic conditions to give product IV. Preferredconditions for this deprotection are sodium hydroxide in methanol, attemperatures in the range of −20-100° C., suitably −10-8° C. PG may alsobe, for example, a tosyl group, which can be removed under acidicconditions (for example HBr in acetic acid). It should be understoodthat the criteria for selection of a suitable protecting group would beknown to a person skilled in the art as described in Protective Groupsin Organic Chemistry, ed. McOmie, J. F. W. Plenum Press, 1973; andGreene, T. W. & Wuts, P. G. M., Protective Groups in Organic Synthesis,John Wiley & Sons, 1991.

It should be noted that, in the series of reactions described above, thepresence of the protecting group PG may not always be necessary,depending upon the exact nature of any substituents present. In suchcases compounds of Formula IV could be obtained directly from compoundsof Formula A where PG is replaced with H. In this case the reaction mayproceed under either acidic or basic conditions. When the reaction iscarried out in basic conditions, typically regioisomer C is the soleproduct isolated. Suitable basic conditions include the use of organicamines such as pyrrolidine or piperidine in solvents such as methanol,ethanol and the like. Preferred basic conditions are pyrrolidine inethanol at a refluxing temperature.

Compounds of Formula H (i.e. compounds of Formula IV in which R is agroup of Formula III, Z is a nitrogen atom and ----- are single bonds)may be prepared as shown in Scheme 4, below. Compounds E or F, whereinPG is a suitable protecting group such as acetate or tosyl, may bereacted with bicyclic piperazine G in the presence of a catalytic amountof an acid, such as p-toluenesulfonic acid or camphorsulfonic acid, thereaction being carried out in an inert solvent such as toluene orbenzene, at temperatures in the range of 25-120° C., to providecompounds H. Preferred conditions are p-toluenesulfonic acid in tolueneat a refluxing temperature. Compound H can be deprotected, as previouslydescribed, to provide compound J.

Bicyclic piperidinones B and piperazines G are either commerciallyavailable or can be prepared using procedures known in the art. Forexample, bicyclic piperidinones of Formula B may be prepared accordingto procedures described in King, F. D., J. Chem. Soc. Perkin Trans. I,1986:447-453 and bicyclic piperazines of Formula G may be preparedaccording to procedures described in Power, P. et al., U.S. Pat. No.5,576,314; Saleh, M. A. et al. J. Org. Chem. 58, 1993:690-695; Urban, F.J. Heterocyclic Chem. 32, 1995:857-861; Bright, G. et al. WO 90/08148;de Costa, B. R. et al. J. Med. Chem. 36, 1993:2311-2320; and Botre, C.et al. J . Med . Chem . 29, 1986:1814-1820.

Compounds of Formula I in which R is a group of Formula II may beprepared in an analogous fashion, as shown in Scheme 5, below.Condensation of azaindole K with an appropriately-substituted piperidonegives compound L, which may be reduced to give compound M (or,alternatively, derivatized to yield compound O). Again, M can exist inisomeric forms, which may be separable by chromatography. Compound M canbe derivatized as previously described to give the desired product N.

The starting azaindoles in the above synthetic schemes may be purchased(in the case of 7-azaindole) or prepared by techniques well known in theart. For example, 4-Azaindoles may be prepared according to the methodof Sakamoto et al., Chem. Pharm. Bull., 34, 1986, p2362-2368.5-Azaindoles may be prepared according to the method of Sakamoto et al.,Heterocycles, 34, 1992, p2379-2384; or, alternatively, according to themethod of Hands, et al., Synthesis, 1996, p877-882. This latter methodcan also be used to prepare 6- and 7-azaindoles.

It should be noted that one skilled in the art would realize that thesequence of reactions described above for the preparation of compoundsof Formula I can be varied. For example, the R₁ group may beincorporated into the molecule before the addition of the group at theindole 3-position.

In some cases, the chemistries outlined above may have to be modified,for instance by use of protecting groups, to prevent side reactions dueto reactive groups, such as reactive groups attached as substituents.This may be achieved be means of conventional protecting groups, asdescribed in Protective Groups in Organic Chemistry, ed. McOmie, J. F.W. Plenum Press, 1973; and Greene, T. W. & Wuts, P. G. M., ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991.

In another of its aspects, the present invention provides compounds ofFormula IV. Whilst certain compounds of Formula IV also bind to the5-HT₆ receptor such compounds are more generally useful as intermediatesin the preparation of compounds of Formula I.

and a salt, solvate or hydrate thereof, wherein

R represents a group of Formula II or Formula III;

one of A, B D or E is a N atom, the remainder being CH groups;

R₂, R₃ and R₄ are independently selected from the group consisting of Hand alkyl;

----- represents a single or double bond, with the proviso that there isonly one double bond in the ring at a time;

n is an integer of from 1-3;

Z is selected from the group consisting of C, CH and N, provided thatwhen ----- is a double bond, Z is C and when ----- is a single bond, Zis selected from CH and N.

Compounds of Formula IV can be converted into compounds of Formula I asshown above.

Certain compounds of Formula I also bind to the 5-HT₇ receptor, and afurther object of the invention provides compounds (for example5-azaindoles wherein R is a saturated group of Formula III) having mixed5-HT₆ and 5-HT₇ activity.

In a further embodiment of the invention, compounds of Formula I can beused to distinguish 5-HT₆ receptors from other receptor subtypes, forexample glutamate or opioid receptors, within a population of receptors,and in particular to distinguish between the 5-HT₆ and other 5-HTreceptor subtypes. The latter can be achieved by incubating preparationsof the 5-HT₆ receptor and one of the other 5-HT receptor subtypes (forexample 5-HT_(2A)) with a 5-HT₆-selective compound of the invention andthen incubating the resulting preparation with a radiolabeled serotoninreceptor ligand, for example [³H]-serotonin. The 5-HT₆ receptors arethen distinguished by determining the difference in membrane-boundactivity, with the 5-HT₆ receptor exhibiting lesser radioactivity, i.e.,lesser [³H]-serotonin binding, than the other 5-HT receptor subtype.

In another embodiment of the invention, a compound of Formula I isprovided in labeled form, such as radiolabeled form, e. g. labeled byincorporation within its structure ³H or ¹⁴C or by conjugation to ¹²⁵I.In another aspect of the invention, the compounds in labeled form can beused to identify 5-HT₆ receptor ligands by techniques common in the art.This can be achieved by incubating the receptor or tissue in thepresence of a ligand candidate and then incubating the resultingpreparation with an equimolar amount of radiolabeled compound of theinvention such as. 5-HT₆ receptor ligands are thus revealed as thosethat are not significantly displaced by the radiolabeled compound of thepresent invention. Alternatively, 5-HT₆ receptor ligand candidates maybe identified by first incubating a radiolabeled form of a compound ofthe invention then incubating the resulting preparation in the presenceof the candidate ligand. A more potent 5-HT₆ receptor ligand will, atequimolar concentration, displace the radiolabeled compound of theinvention.

A radiolabelled compound of Formula I may be prepared using standardmethods known in the art. For example a compound of Formula I wherein Aris substituted with a radioactive iodo group may be prepared from thecorresponding trialkyltin (suitably trimethyltin) derivative usingstandard iodination conditions, such as [¹²⁵I] sodium iodide in thepresence of chloramine-T in a suitable solvent, such asdimethylformamide. The trialkyltin compound may be prepared from thecorresponding non-radioactive halo, suitably iodo, compound usingstandard palladium-catalyzed stannylation conditions, for examplehexamethylditin in the presence of tetrakis(triphenylphosphine)palladium (0) in an inert solvent, such as dioxane, and at elevatedtemperatures, suitably 50-100° C. Alternatively, tritium may beincorporated into a compound of Formula I using standard techniques, forexample by hydrogenation of a suitable precursor to a compound ofFormula I using tritium gas and a catalyst.

Compounds of Formula I are useful as pharmaceuticals for the treatmentof various conditions in which the use of a 5-HT₆ antagonist isindicated, such as psychosis, schizophrenia, manic depression,depression, neurological disturbances, memory disturbances,Parkinsonism, amylotrophic lateral sclerosis, Alzheimer's disease andHuntington's disease. In another of its aspects, the present inventionprovides pharmaceutical compositions useful to treat 5-HT₆-relatedmedical conditions, in which a compound of Formula I is present in anamount effective to antagonize 5-HT₆ receptor stimulation, together witha pharmaceutically acceptable carrier. In a related aspect, theinvention provides a method for treating medical conditions for which a5-HT₆ receptor antagonist is indicated, which comprises the step ofadministering to the patient an amount of a compound of Formula Ieffective to antagonize 5-HT₆ receptor stimulation, and apharmaceutically acceptable carrier therefor.

For use in medicine, the compounds of the present invention can beadministered in a standard pharmaceutical composition. The presentinvention therefore provides, in a further aspect, pharmaceuticalcompositions comprising a pharmaceutically acceptable carrier and aFormula I compound or a pharmaceutically acceptable salt, solvate orhydrate thereof, in an amount effective to treat the target indication.

The compounds of the present invention may be administered by anyconvenient route, for example by oral, parenteral, buccal, sublingual,nasal, rectal, patch, pump or transdermal administration and thepharmaceutical compositions formulated accordingly.

Compounds of Formula I and their pharmaceutically acceptable salts whichare active when given orally can be formulated as liquids, for examplesyrups, suspensions or emulsions, or as solid forms such as tablets,capsules and lozenges. A liquid formulation will generally consist of asuspension or solution of the compound or pharmaceutically acceptablesalt in a suitable pharmaceutical liquid carrier for example, ethanol,glycerine, non-aqueous solvent, for example polyethylene glycol, oils,or water with a suspending agent, preservative, flavouring or colouringagent. A composition in the form of a tablet can be prepared using anysuitable pharmaceutical carrier routinely used for preparing solidformulations. Examples of such carriers include magnesium stearate,starch, lactose, sucrose and cellulose. A composition in the form of acapsule can be prepared using routine encapsulation procedures. Forexample, pellets containing the active ingredient can be prepared usingstandard carriers and then filled into a hard gelatin capsule;alternatively, a dispersion or suspension can be prepared using anysuitable pharmaceutical carrier, for example aqueous gums, celluloses,silicates or oils and the dispersion or suspension filled into a softgelatin capsule.

Typical parenteral compositions consist of a solution or suspension ofthe compound or pharmaceutically acceptable salt in a sterile aqueouscarrier or parenterally acceptable oil, for example polyethylene glycol,polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.Alternatively, the solution can be lyophilized and then reconstitutedwith a suitable solvent just prior to administration.

Compositions for nasal administration may conveniently be formulated asaerosols, drops, gels and powders. Aerosol formulations typicallycomprise a solution or fine suspension of the active substance in aphysiologically acceptable aqueous or non-aqueous solvent and areusually presented in single or multidose quantities in sterile form in asealed container, which can take the form of a cartridge or refill foruse with an atomising device. Alternatively, the sealed container may bea unitary dispensing device such as a single dose nasal inhaler or anaerosol dispenser fitted with a metering valve which is intended fordisposal after use. Where the dosage form comprises an aerosoldispenser, it will contain a propellant which can be a compressed gassuch as compressed air or an organic propellant such asfluorochlorohydrocarbon. The aerosol dosage forms can also take the formof a pump-atomizer.

Compositions suitable for buccal or sublingual administration includetablets, lozenges, and pastilles, wherein the active ingredient isformulated with a carrier such as sugar, acacia, tragacanth, or gelatinand glycerine. Compositions for rectal administration are convenientlyin the form of suppositories containing a conventional suppository basesuch as cocoa butter.

Preferably, the composition is in unit dose form such as a tablet,capsule or ampoule. Suitable unit dosages, i.e. therapeuticallyeffective amounts, can be determined during clinical trials designedappropriately for each of the conditions for which administration of achosen compound is indicated and will of course vary depending on thedesired clinical endpoint. Each dosage unit for oral administration maycontain from 0.01 to 500 mg/kg (and for parenteral administration maycontain from 0.1 to 50 mg) of a compound of Formula I, or apharmaceutically acceptable salt thereof calculated as the free base,and will be administered in a frequency appropriate for initial andmaintenance treatments. For laboratory use, the present compounds can bestored in packaged form for reconstitution and use.

EXPERIMENTAL EXAMPLES Example 13-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-5-azaindole

A mixture of 5-azaindole (0.5 g, 4.23 mmol),1,2,3,5,6,8,8a-heptahydrohydro-7-oxo-indolizine (589 mg, 4.23 mmol) andpyrrolidine (3.0 g, 42.3 mmol) in ethanol (4 mL) were heated to refluxfor 6 hrs. The reaction mixture was cooled, filtered, and the collectedsolid washed with ether to give3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (0.521 g,51.6%).

In a similar fashion, the following compounds were prepared:

3-(1,2,4,6,7,9a-Hexahydro-2H-quinolizine-2-yl)-5-azaindole (0.167 g,50.6%); from 5-azaindole (154 mg, 1.3 mmol), octahydro-quinolizine-2-one(200 mg, 1.3 mmol) and pyrrolidine (0.7 mL) in ethanol (1.2 mL), heatingat reflux overnight.

3-(1-Methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-azaindole (1.754 g, 49%);from 5-azaindole (2.0 g, 16.9 mmol); N-methyl-4-piperidone (1.92 g ,16.9 mmol) and pyrrolidine (12.04 g, 169 mmol) in ethanol (20 mL).

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-4-azaindole (792 mg, 39%);from 4-azaindole (1.0 g, 8.46 mmol),1,2,3,5,6,8,8a-heptahydrohydro-7-oxo-indolizine (1.77 g, 12.7 mmol) andpyrrolidine (3.5 g, 42.3 mmol) in ethanol (8 mL), heating at reflux for3hrs.

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-6-azaindole (273 mg, 53.9%);from 6-azaindole (250 mg, 2.1 mmol),1,2,3,5,6,8,8a-heptahydrohydro-7-oxo-indolizine (324 mg, 2.3 mmol) andpyrrolidine (1.2 g, 16.9 mmol) in ethanol (2 mL) heating at reflux for 6hrs.

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-7-azaindole (396 mg, 39.3%);from 7-azaindole (500 mg, 4.2 mmol),1,2,3,5,6,8,8a-heptahydrohydro-7-oxo-indolizine (589 mg, 4.2 mmol) andpyrrolidine (3.0 g, 42 mmol) in ethanol (4 mL) heating at reflux for 5hrs.

Example 21-(2-Chlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole.

To a THF (1 mL) solution of3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-5-azaindole (10 mg, 0.0418mmol) at RT, 1M NaN(TMS)₂ (100,μL, 0.1 mmol) was added and the mixturestirred for 10 mins. 2-chlorobenzoyl chloride (13 μL, 0.103 mmol) wasadded and the reaction mixture stirred overnight. After dilution withdichloromethane, purification by column chromatography with 2% methanol(2M/NH₃) in dichloromethane gave1-(2-chlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole(8.9 mg, 56.4%).

In a similar fashion, the following compounds were prepared:

1-(2,6-Dichlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole(4.2 mg, 24.4%); from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418mmol), 2-chlorobenzoyl chloride (13 μL, 0.0907 mmol) and 1M NaN(TMS)₂(100 μL, 0.10 mmol) in THF (1 mL) at RT.

1-(2,6-Dimethoxylbenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole(9.4 mg, 55.8%); from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418mmol), 2,6-dimethoxylbenzoyl chloride (20 mg, 0.0997 mmol) and 1MNaN(TMS)₂ (100 μL, 0.10 mmol) in THF (1 mL) at RT.

1-Benzoyl-3-(1,2,3,5,68,8a-hexahydro-7-indolizinyl)-5-azaindole (5.8 mg,41.5%); from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10mg, 0.0418 mmol), benzoyl chloride (13 μL, 0.12 mmol) and 1M NaN(TMS)₂(100 μL, 0.10 mmol) in THF (1 mL) at RT.

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-benzenesulfonyl-5-azaindole(4.8 mg, 30.3%); from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418mmol), benzenesulfonyl chloride (20 mg, 0.113 mmol) and 1M NaN(TMS)₂(100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

1-(4-Fluorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole(5.9 mg, 35.5%); from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418mmol), 4-fluorobenzenesulfonyl chloride (20 mg, 0.103 mmol) and 1MNaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

1-(4-Chlorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl-5-azaindole(6.3 mg, 36.4%); from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418mmol), 4-chlorobenzenesulfonyl chloride (20 mg, 0.095 mmol) and 1MNaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(4-methylbenzenesulfonyl)-5-azaindole(8.9 mg, 54.1%); from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418mmol), 4-methyl-benzenesulfonyl chloride (20 mg, 0.105 mmol) and 1MNaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-5-azaindole(8.9 mg, 49.6%); from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole (10 mg, 0.0418mmol), 1-naphthalenesulfonyl chloride (20 mg, 0.088 mmol) and 1MNaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-5-azaindole(8.3 mg, 46.2%); 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole(10 mg, 0.0418 mmol), 2-naphthalenesulfonyl chloride (20 mg, 0.088 mmol)and 1M NaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

3-(Octahydro-7-indolizinyl)-1-benzenesulfonyl-5-azaindole (11.9 mg,75.3%); from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10 mg, 0.0415mmol), benzene-sulfonyl chloride (12 μL, 0.094 mmol) and 1M NaN(TMS)₂(100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-5-azaindole (15.4mg, 86%); from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10 mg,0.0415 mmol), 1-naphthalenesulfonyl chloride (15 mg, 0.072 mmol) and 1MNaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT. The two enantiomerswere separated by Chiral chromatography (Chiracel OD).3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-5-azaindole (17.5mg, 97.7%); from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10 mg,0.0415 mmol), 2-naphthalenesulfonyl chloride (15 mg, 0.072 mmol) and 1MNaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5mL) at RT.

3-(Octahydro-7-indolizinyl)-2,5-dichlorobenzenesulfonyl-5-azaindole(17.5 mg, 99.8%); from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10mg, 0.0415 mmol), 2,5-dichlorobenzenesulfonyl chloride (15 mg, 0.061mmol) and 1M NaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

3-(Octahydro-7-indolizinyl)-1-benzenesulfonyl-5-azaindole (10.3 mg,65.2%); from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10 mg, 0.0415mmol), benzene sulfonyl chloride (10 μL, 0.0784 mmol) and 1M NaN(TMS)₂(100 μL, 0.1 mmol) in THF (0.5 mL) at RT.

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-5-azaindole (14.3mg, 79.9%); from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10 mg,0.0415 mmol), 1-naphthalenesulfonyl chloride (17.2 mg, 0.0828 mmol) and1M NaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-5-azaindole (10.7mg, 59.8%); from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10 mg,0.0415 mmol), 2-naphthalenesulfonyl chloride (17.2 mg, 0.0828 mmol) and1M NaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

3-(Octahydro-7-indolizinyl)-2,5-dichlorobenzenesulfonyl-5-azaindole(12.3 mg, 70.3%); from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10mg, 0.0415 mmol), 2,5-dichlorobenzenesulfonyl chloride (20.3 mg, 0.0827mmol) and 1M NaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

1-Naphthalenesulfonyl-3-(octahydro-8-quinolizinyl)-5-azaindole (lesspolar isomer 71.2 mg, 37.7%) and1-naphthalenesulfonyl-3-(octahydro-quinolizine)-5-azaindole (more polarisomer) (48.3 mg, 25.6%); from 3-(octahydro-quinolizine)-1-H-5-azaindole(102 mg, 0.42 mmol), 1-naphthalenesulfonyl chloride (176 mg, 0.84 mmol)and 1M NaN(TMS)₂ (800 μL, 0.10 mmol) in THF (4 mL) at 10° C.

3-(1-Methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1-benzenesulfonyl-5-azaindole(28.5 mg, 86%); from3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-azaindole (20 mg, 0.094mmol), benzenesulfonyl chloride (24 μL, 0.188 mmol) and 1M NaN(TMS)₂(250 μL, 0.25 mmol) in THF (1 mL) at RT.

1-(2,6-Dichlorobenzoyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-azaindole(34.8 mg, 96%); from3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)5-azaindole (20 mg, 0.094mmol), 2,6-dichlorobenzoyl chloride (27 μL, 0.188 mmol) and 1M NaN(TMS)₂(250 μL, 0.25 mmol) in THF (1 mL) at RT.

3-(1-Methyl-4-piperidinyl)-1-benzenesulfonyl-5-azaindole (21.0 mg, 64%);from 3-(1-methyl-4-piperidinyl)-5-azaindole (20 mg, 0.094 mmol),benzenesulfonyl chloride (24 μL, 0.188 mmol) and 1M NaN(TMS)₂ (250 μL,0.25 mmol) in THF (1 mL) at RT.

1-(2,6-Dichlorobenzoyl)-3-(1-methyl-4-piperidinyl)-5-azaindole (8.3 mg,23%); from 3-(1-methyl-4-piperidinyl)-5-azaindole (20 mg, 0.094 mmol),2,6-dichlorobenzoyl chloride (27 μL, 0.188 mmol) and 1M NaN(TMS)₂ (250μL, 0.25 mmol) in THF (1 mL) at RT.

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-4-azaindole (13mg, 72.7%); from 3-(octahydro-7-indolizinyl)-1-H-4-azaindole (10 mg,0.0415 mmol), 1-naphthalenesulfonyl chloride (17.3 mg, 0.083 mmol) and1M NaN(TMS)₂ (100 μL, 0.10 mmol) in THF (1 mL) at RT.

3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-4-azaindole (12.2mg, 68.3%); from 3-(octahydro-7-indolizinyl)-1-H-4-azaindole (10 mg,0.0415 mmol), 2-naphthalenesulfonyl chloride (17.3 mg, 0.083 mmol) and1M NaN(TMS)₂ (100 μL, 0.10 mmol) in THF (1 mL) at RT.

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-4-azaindole (11mg, 28%); from 3-(octahydro-7-indolizinyl)-1-H-4-azaindole (more polarisomer) (22 mg, 0.091 mmol), 1-naphthalenesulfonyl chloride (38 mg, 0.18mmol) and 1M NaN(TMS)₂ (200 μL, 0.10 mmol) in THF (2.5 mL) at RT.

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-6-azaindole (8.9mg, 43.2%); from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-6-Azaindole(12 mg, 0.055 mmol), 1-naphthalenesulfonyl chloride (20.9 mg, 0.1 mmol)and 1M NaN(TMS)₂ (100 μL, 0.10 mmol) in THF (1 mL) at RT.

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-6-azaindole (16.1mg, 78%); from 3-(octahydro-7-indolizinyl)-1-H-4-azaindole (less polarisomer) (12 mg, 0.05 mmol), 1-naphthalenesulfonyl chloride (20.9 mg, 0.1mmol) and 1M NaN(TMS)₂ (100 μL, 0.10 mmol) in THF (1 mL) at RT.

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-6-azaindole (7.8mg, 38 %); from 3-(octahydro-7-indolizinyl)-1-H-4-azaindole (more polarisomer) (12 mg, 0.05 mmol), 1-naphthalenesulfonyl chloride (20.9 mg, 0.1mmol) and 1M NaN((TMS)₂ (100 μL, 0.10 mmol) in THF (1 mL) at RT.

1-(2,6-Dichlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindole(8.8 mg, 51.1%); from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418mmol), 2-chlorobenzoyl chloride (13 μL, 0.0907 mmol) and 1M NaN(TMS)₂(100 μL, 0.10 mmol) in THF (1 mL) at RT.

1-(2,6-Dimethoxylbenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindole(2.0 mg, 11.9%); from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418mmol), 2,6-dimethoxylbenzoyl chloride (20 mg, 0.0997 mmol) and 1MNaN(TMS)₂ (100 μL, 0.10 mmol) in THF (1 mL) at RT.

1-Benzoyl-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindole (8.1 mg,58.0%); from 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10mg, 0.0418 mmol), benzoyl chloride (13 μL, 0.12 mmol) and 1M NaN(TMS)₂(100 μL, 0.10 mmol) in THF (1mL) at RT.

3-(1,2,3,5,8, 8a-Hexahydro-7-indolizinyl)- 1-benzenesulfonyl-7-azaindole(6.9 mg, 43.5%); from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418mmol), benzenesulfonyl chloride (20 mg, 0.113 mmol) and 1M NaN(TMS)₂(100 μL, 0.10 mmol) in THF (0.5 mL) at RT

1-(4-Fluorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindole(9.1 mg, 54.8 %); from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418mmol), 4-fluorobenzenesulfonyl chloride (20 mg, 0.103 mmol) and 1MNaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

1-(4-Chlorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl-7-azaindole(10.2 mg, 58.9%); from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418mmol), 4-fluorobenzenesulfonyl chloride (20 mg, 0.095 mmol) and 1MNaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(4-methyl-benzenesulfonyl)-7-azaindole(6.9 mg, 42.0%); from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418mmol), 4-methyl-benzenesulfonyl chloride (20 mg, 0.105 mmol) and 1MNaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-7-azaindole(8.4 mg, 46.8%); from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418mmol), 1-naphthalenesulfonyl chloride (20 mg, 0.088 mmol) and 1MNaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-7-azaindole(9.4 mg, 52.4%); from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-7-Azaindole (10 mg, 0.0418mmol), 2-naphthalenesulfonyl chloride (20 mg, 0.088 mmol) and 1MNa((TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

3-(Octahydro-7-indolizinyl)-1-benzenesulfonyl-7-azaindole (14.4 mg,91.1%); from 3-(octahydro-7-indolizinyl)-1H-7-azaindole (less polarisomer) (10 mg, 0.0415 mmol), benzenesulfonyl chloride (10 μL, 0.0784mmol) and 1M NaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-7-azaindole (17.8mg, 99%); from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (less polarisomer) (10 mg, 0.0415 mmol), 1-naphthalenesulfonyl chloride (17.2 mg,0.0828 mmol) and 1M NaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-7-azaindole (15.3mg, 85.5%); from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (less polarisomer) (10 mg, 0.0415 mmol), 2-naphthalenesulfonyl chloride (17.2 mg,0.0828 mmol) and 1M NaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

3-(Octahydro-7-indolizinyl)-2,5-dichlorobenzenesulfonyl-5-azaindole(14.2 mg, 81%); from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (lesspolar isomer) (10 mg, 0.0415 mmol), 2,5-dichlorobenzenesulfonyl chloride(20.3 mg, 0.0827 mmol) and 1M NaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5mL) at RT.

3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-7-azaindole (9.1mg, 50.8%); from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (more polarisomer) (8 mg, 0.033 mmol), 1-naphthalenesulfonyl chloride (15 mg, 0.072mmol) and 1M NaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-7-azaindole (9.4mg, 85.5%); from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (more polarisomer) (8 mg, 0.033 mmol), 2-naphthalenesulfonyl chloride (15 mg, 0.072mmol) and 1M NaN(TMS)₂ (100 μL, 0.10 mmol) in THF (0.5 mL) at RT.

Example 33-(1-Methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1-benzenesulfonyl-7-azaindole

Sodium bis(trimethylsilyl)amide (0.2 mL, 1M in THF, 0.23 mmol) was addedto a solution of 3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole(24.9 mg, 0.12 mmol) in THF (2.5 mL) at −78° C. and the mixture stirredfor 1 h. Benzenesulfonyl chloride (30 μL, 0.24 mmol) was added and themixture stirred at room temperature for 2 h, prior to quenching withwater (4 drops) and silica gel (˜1 g). Purification using solid phaseextraction tubes (1000 mg silica, eluting with 0-10% 2M methanolicammonia in dichloromethane) yielded3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1-benzenesulfonyl-7-azaindole(21.3 mg, 51%, HRMS-FAB⁺ for C₁₉H₁₉N₃O₂S: calculated MH⁺:354.12762;found:354.12896).

In a like manner, the following additional compounds were prepared:

1-(4-Methoxybenzenesulfonyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole;(24.1 mg, 54%); from3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole (24.9 mg,0.12 mmol) and 4-methoxybenzenesulfonyl chloride (48.2 mg, 0.23 mmol);HRMS-FAB⁺ for C₂₀H₂₁N₃O₃S: calculated MH⁺:384.13818; found:384.13811.

1-(4-Fluorobenzenesulfonyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole;(21.1 mg, 48%); from3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole (24.9 mg,0.12 mmol) and 4-fluorobenzenesulfonyl chloride (47 mg, 0.24 mmol);HRMS-FAB⁺ for C₁₉H₁₈N₃O₂SF: calculated MH⁺:372.11819; found:372.11690.

1-Benzoyl-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole; (6.7mg, 18%); from3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole (25.0 mg,0.12 mmol) and benzoyl chloride (28 μL, 0.24 mmol); HRMS-FAB⁺ forC₂₀H₁₉N₃O: calculated MH⁺:318.16064; found:318.16191.

1-(4-Methoxybenzoyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole;(16.4 mg, 41%); from3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole (24.8 mg,0.12 mmol) and 4-methoxybenzoyl chloride (35 μL, 0.24 mmol); HRMS-FAB⁺for C₂₁H₂₁N₃O₂: calculated MH⁺:348.17120; found:348.16994.

1-(4-Fluorobenzoyl)-3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-7-azaindole;(10.1 mg, 26%); from3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-1H-7-azaindole (24.8 mg,0.12 mmol) and 4-fluorobenzoyl chloride (28 μL, 0.24 mmol); HRMS-FAB⁺for C₂₀H₁₈N₃OF: calculated MH⁺:336.15121; found:336.15100.

Example 4 3-(Octahydro-7-indolizinyl)-1H-5-Azaindole

A mixture of 3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-1H-5-Azaindole(400 mg, 1.67 mmol) and 10% Pd/C (400 mg) in ethanol (15 mL) was stirredunder H₂ overnight. The reaction mixture was filtered and the filtrateconcentrated and purified by column chromatography. Elution with 5%methanol (2M/NH₃) in dichloromethane gave the less polar isomer (297.7mg, 73.5%) and with 10% methanol (2M/NH₃) in dichloromethane gave themore polar isomer (73 mg, 18.1%).

In a similar fashion, the following compounds were prepared:

3-(Octahydro-quinolizine)-1H-5-Azaindole (95.5 mg, 79%); from3-(1,2,4,6,7,9a-hexahydro-2H-quinolizine-2-yl)-5-azaindole (120 mg,0.474 mmol) and 10% Pd/C (120 mg) in ethanol (2 mL) under H₂ overnight.

3-(1-Methyl-4-piperidinyl)-5-azaindole (0.557 g, 76%); from3-(1-methyl-1,2,3,6-tetrahydro-4-pyridinyl)-5-azaindole (0.725 g, 3.4mmol) and 10% Pd/C (0.45 g, 2.04 mmol) in ethanol (8 mL) underH₂overnight.

3-(Octahydro-7-indolizinyl)-1H-4-azaindole (less polar isomer 378 mg,75%; and more polar isomer 111 mg, 22%) from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-4-azaindole (500 mg, 2. mmol)and 10% Pd/C (290 mg) in ethanol (10 mL) under H₂ overnight.

3-(Octahydro-7-indolizinyl)-1H-6-azaindole (less polar isomer 87 mg,72%; and more polar isomer 34 mg, 28%); from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-6-azaindole (120 mg, 0.5 mmol)and 10% Pd/C (100 mg) in ethanol (2 mL) under H₂ overnight.

3-(Octahydro-7-indolizinyl)-1H-7-azaindole (less polar isomer 134.2 mg,49.5% and more polar isomer 36.6 mg, 13.3%); from3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-6-azaindole (270 mg, 1.13 mmol)and 10% Pd/C (300 mg) in ethanol (4 mL) under H₂ overnight.

Example 4 Binding Affinity for the 5-HT₆ Receptor

All of the compounds of the invention were evaluated using cell typesreceptive specifically to the 5-HT₆ receptor (for cloning andcharacterization of the human 5-HT₆ receptor see Kohen, et al. J.Neurochemistry, 66, 1996: 47-56). The assay protocol generally entailedthe incubation of membranes prepared from cells expressing the 5-HT₆receptor with ³H-LSD (2nM). Increasing levels of the test compound wereincubated with the radioligand and the membrane homogenates preparedfrom the recombinant cells. After a 60 minute incubation at 37° C., theincubation was terminated by vacuum filtration. The filters were washedwith buffer and the filters were counted for radioactivity using liquidscintillation spectrometry. The affinity of the test compound for the5-HT₆ receptor was determined by computer-assisted analysis of the dataand determining the amount of the compound necessary to inhibit 50% ofthe binding of the radioligand to the receptor. Concentrations rangingfrom 10⁻¹¹ M to 10⁻⁵ M of the test compound were evaluated. Forcomparison, the affinity of clozapine (Ki=3 nM) for the 5-HT₆ receptorwas used as a standard. Affinity for the 5-HT₆ receptor is expressed asthe amount (in percent) of binding of the radioligand that is inhibitedin the presence of 100 nM of test compound. A greater percent inhibitionindicates greater affinity for the 5-HT₆ receptor.

Selected compounds of the invention showed an percent inhibition ofgreater than 50% for the 5-HT₆ receptor.

Specific compounds of the invention, for example1-(1-Naphthalenesulfonyl)-3-(octahydro-7-indolizinyl)-4-azaindole;1-(1-Naphthalenesulfonyl)-3-(octahydro-8-quinolizinyl)-5-azaindole (frommore polar isomer);1-(1-Naphthalenesulfonyl)-3-(octahydro-7-indolizinyl)-6-azaindole (lesspolar isomer) and1-(2-Naphthalenesulfonyl)-3-(octahydro-7-indolizinyl)-7-azaindole (frommore polar isomer) showed a percent inhibition of greater than 80% forthe 5-HT₆ receptor.

More specific compounds of the invention, for example,1-(2-Naphthalenesulfonyl)-3-(octahydro-7-indolizinyl)-4-azaindole;3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-5-azaindole;1-(1-Naphthalenesulfonyl)-3-(octahydro-7-indolizinyl)-6-azaindole (lesspolar isomer) and1-(2-Naphthalenesulfonyl)-3-(octahydro-7-indolizinyl)-7-azaindole (frommore polar isomer) showed a percent inhibition of greater than 95% forthe 5-HT₆ receptor.

In terms of selectivity, selected compounds of the invention showed anpercent inhibition of greater than 50% for the 5-HT₆ receptor and alsohad a percent inhibition less than 50% for other serotonin receptors,specifically the 5-HT_(2A), 5HT_(2C) and 5-HT₇ receptors.

Specific compounds, for example3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(4-methylbenzenesulfonyl)-5-azaindole;1-(1-Naphthalenesulfonyl)-3-(octahydro-7-indolizinyl)-6-azaindole (morepolar isomer) and1-(2,6-Dichlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindoleshowed a percent inhibition of greater than 80% for the 5-HT₆ receptorand less than 20% for the 5-HT_(2A), 5HT_(2C) and 5-HT₇ receptors.

More specific compounds, for example1-(1-Naphthalenesulfonyl)-3-(octahydro-7-indolizinyl)-4-azaindole (morepolar isomer);3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-benzenesulfonyl-5-azaindoleand3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-7-azaindoleshowed a percent inhibition of greater than 90% for the 5-HT₆ receptorand less than 10% for the 5-HT_(2A), 5HT_(2C) and 5-HT₇ receptors

Example 5 Functional Assay

The 5HT₆ receptor responds to serotonin and other agonists by increasingadenyl cyclase mediated production of cyclic AMP. Particular testcompounds were assayed for their effect on adenyl cyclase activity usingthe procedure described below.

Compounds acting as antagonists at the 5HT₆ receptor will antagonize theagonist effect of serotonin and thus, will block the serotonin-inducedincrease in adenyl cyclase activity.

HEK 293 cells stably expressing the human 5HT₆ receptor were plated in 6well plates in DMEM (Dulbecco's Modified Eagle Medium)/F12 (NutrientMixture F12-Ham) media with 10% FCS (fetal calf serum) and G418(Geneticen Disulfate, 500 ug/ml), and incubated at 37° C. in a CO₂incubator. The cells were allowed to grow to about 70% confluence beforeuse in the assay.

The culture medium of each well was removed, and the wells were washedonce with serum free media. Then 2 ml of SFM+IBMX medium (SFM with 0.5mM IBMX, 3-isobutyl-1-methylxanthine, 0.1% ascorbic acid and 10 mMpargyline) was added to each well and the wells were incubated at 37° C.for 10 min. Following incubation, the SFM+IBMX medium was removed fromeach well and fresh SFM+IBMX media was added to the wells separatelywith one of a) serotonin (1 μM final concentration); b) test compound(100 nM and 10 μM, to test for agonist activity); and c) test compound(100 nM and 10 μM) along with serotonin (μM final concentration, to testfor antagonist activity). Basal adenyl cyclase activity was determinedfrom wells with only SFM+IBMX media added.

The cells were then incubated at 37° C. for 30 minutes in a CO₂incubator. Following incubation, the media were removed from each well.The wells were washed once with 1 ml of PBS (phosphate buffered saline).Each well was then treated with 1 mL cold 95% ethanol:5 mM EDTA (2:1) at4° C. for 1 hour. The cells from each well were then scraped andtransferred into individual Eppendorf tubes. The tubes were centrifugedfor 5 minutes at 4° C., and the supernatants were transferred to newEppendorf tubes and stored at 4° C. The pellets were discarded and thesupernatants were stored at 4° C. until assayed for cAMP concentration.cAMP content for each extract was determined in duplicate by EIA(enzyme-immunoassay) using the Amersham Biotrak cAMP EIA kit (AmershamRPN 225). Final results were expressed as % basal response for agonistsand % reversal of serotonin response for antagonists.

The total stimulation of adenyl cyclase by serotonin (S_(o)) wasdetermined as the difference in concentration of cAMP in theserotonin-treated cells (C_(d)) and the basal-treated cells (C_(f)).

S _(o) =C _(f) −C _(d)

The net stimulation (S) of basal adenyl cyclase by an agonist testcompound was determined as the difference in cAMP concentration in thedrug-treated cell (C) and the basal-treated cells (C_(f)).

S=C _(f) −C

The net stimulation (S_(s)) of basal adenyl cyclase by serotonin in thepresence of an antagonist test compound was determined as the differencein cAMP concentration in the serontonin-drug-treated cells (C_(s)) andthe basal-treated cells (C_(f)).

S _(s) =C _(f) −C _(s)

The ability of the antagonist test compound to reverse the serotoninstimuation of adenyl cyclase activity (% reversal, % R) was determinedby the formula:

% R=(1−S_(s)/S_(o))×100

Selected compounds of the invention, for example1-(benzenesulfonyl)-3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-5-azaindole;1-(benzenesulfonyl)-3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-7-azaindole;3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-5-azaindoleand3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-7-azaindole,were able to reverse the serotonin stimulation of adenyl cyclase andthus were shown to behave as a 5-HT₆ receptor antagonists.

We claim:
 1. A compound of formula I, or a salt, solvate or hydratethereof

wherein R is a group of formula III

one of A, B, D and E is a N atom, the remainder being CH groups; R₁ isselected from the group consisting of SO₂Ar, C(O)Ar, CH₂Ar and Ar; R₂and R₃ are independently selected from the group consisting of H andalkyl; ----- is a single or double bond, with the proviso that there isat most one double bond in the ring; n is an integer of from 1-3; z isselected from the group consisting of C and CH; and Ar is an optionallysubstituted aryl group.
 2. A compound according to claim 1 wherein R₁ isselected from the group consisting of SO₂Ar and C(O)Ar.
 3. A compoundaccording to claim 2 wherein R₁ is SO₂Ar.
 4. A compound according toclaim 3 wherein Ar is selected from the group consisting of substitutedphenyl and naphthyl.
 5. A compound according to claim 4 wherein Ar isnaphthyl.
 6. A compound selected from the group consisting of:3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-4-azaindole;3-(Octahydro-7-indolizinyl)-1H-4-azaindole;3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-4-azaindole;3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-4-azaindole;3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-4-azaindole;1-(2,6-Dichlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole;1-(2,6-Dimethoxylbenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole;1-(2-Chlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole;1-(4-Chlorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl-5-azaindole;1-(4-Fluorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole;1-Benzoyl-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-5-azaindole;1-(1-Naphthalenesulfonyl)-3-(octahydro-8-quinolizinyl)-5-azaindole;3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(4-methylbenzenesulfonyl)-5-azaindole;3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-5-azaindole;3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-5-azaindole;3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-benzenesulfonyl-5-azaindole;3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-5-azaindole;3-(1,2,4,6,7,9a-Hexahydro-2H-quinolizine-2-yl)-5-azaindole;3-(Octahydro-7-indolizinyl)-1H-5-azaindole;3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-5-azaindole;3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-5-azaindole;3-(Octahydro-7-indolizinyl)-1-benzenesulfonyl-5-azaindole;3-(Octahydro-7-indolizinyl)-1-benzenesulfonyl-5-azaindole;3-(Octahydro-7-indolizinyl)-2,5-dichlorobenzenesulfonyl-5-azaindole;3-(Octahydro-7-indolizinyl)-2,5-dichlorobenzenesulfonyl-5-azaindole;3-(Octahydro-7-indolizinyl)-2,5-dichlorobenzenesulfonul-5-azaindole;3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-5-azaindole;3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-5-azaindole;3-(Octahydro-quinolizine)-1H-5-azaindole;3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-6-azaindole;3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-6-azaindole;3-(Octahydro-7-indolizinyl)-1H-6-azaindole;3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-6-azaindole;3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-6-azaindole;1-(2,6-Dichlorobenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindole;1-(2,6-Dimethoxylbenzoyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindole;1-(4-Chlorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl-7-azaindole;1-(4-Fluorobenzenesulfonyl)-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindole;1-Benzoyl-3-(1,2,3,5,8,8a-hexahydro-7-indolizinyl)-7-azaindole;3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(4-methylbenzenesulfonyl)-7-azaindole;3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1H-7-azaindole;3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-7-azaindole;3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-benzenesulfonyl)-7-azaindole;3-(1,2,3,5,8,8a-Hexahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-7-azaindole;3-(Octahydro-7-indolizinyl)-1H-7-azaindole;3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-7-azaindole;3-(Octahydro-7-indolizinyl)-1-(1-naphthalenesulfonyl)-7-azaindole;3-(Octahydro-7-indolizinyl)-1-(1-benzenesulfonyl-7-azaindole;3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-7-azaindole; and3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-7-azaindole.
 7. Apharmaceutical composition suitable for 5-HT₆ receptor antagonism,comprising a compound as claimed in claim 1, or a salt, solvate orhydrate thereof, in combination with a pharmaceutically acceptablecarrier.
 8. A method of treating a patient having a medical conditionfor which a 5-HT₆ receptor antagonist is indicated, comprisingadministering to the patient a 5-HT₆ receptor antagonistic-effectiveamount of a compound as claimed in claim 1, or a salt, solvate orhydrate thereof.